Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro*1

Margaretten, Nadine C.; Hincks, Jeffrey R.; Warren, Reed P.; Coulombe, Roger A.

doi:10.1016/0041-008x(87)90079-2

Cited by 33 publications

(10 citation statements)

References 29 publications

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“…However, phenytoin has a direct protective effect on axons (Fern et al, 1993) and thus it was not possible in the study with EAE mice to differentiate between a direct effect of sodium channel blockade on microglia or reduced microglial activity as a result of less axonal damage. In addition, phenytoin has been reported to effect other cell types that produce indirect actions on the activity of microglia (e.g., Hansen et al, 1988; Margaretten et al, 1987; Okada et al, 2001; Okamoto et al, 1988). The present observations with purified microglia clearly demonstrate a direct effect of sodium channel blockade on the activity of microglia, and suggest that at least a portion of the immunomodulatory effect of phenytoin in mice with EAE is due to a direct action of the sodium channel blocker on microglia.…”

Section: Discussionmentioning

confidence: 99%

Sodium channel activity modulates multiple functions in microglia

Black

Liu

Waxman

2008

Glia

139

149

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Microglia provide surveillance in the central nervous system and become activated following tissue insult. Detailed mechanisms by which microglia detect and respond to their environment are not fully understood, but it is known that microglia express a number of surface receptors and ion channels, including voltage-gated sodium channels, that participate in transduction of external stimuli to intra-cellular responses. To determine whether activated microglia are affected by the activity of sodium channels, we examined the expression of sodium channel isoforms in cultured microglia and the action of sodium channel blockade on multiple functions of activated microglia. Rat microglia in vitro express tetrodotoxin (TTX)-sensitive sodium channels Nav1.1 and Nav1.6 and the TTX-resistant channel Nav1.5, but not detectable levels of Nav1.2, Nav1.3, Nav1.7, Nav1.8, and Nav1.9. Sodium channel blockade with phenytoin (40 microM) and TTX (0.3 microM) significantly reduced by 50-60% the phagocytic activity of microglia activated with lipopolysaccharide (LPS); blockade with 10 microM TTX did not further reduce phagocytic activity. Phenytoin attenuated by approximately 50% the release of IL-1 alpha, IL-1 beta, and TNF-alpha from LPS-stimulated microglia, but had minimal effects on the release of IL-2, IL-4, IL-6, IL-10, MCP-1, and TGF-alpha. TTX (0.3 microM) reduced, but to a smaller extent, the release of IL-1 alpha, IL-1 beta, and TNF-alpha from activated microglia. Phenytoin and TTX also significantly decreased by approximately 50% adenosine triphosphate-induced migration by microglia; studies with microglia cultured from med mice (which lack Nav1.6) indicate that Nav1.6 plays a role in microglial migration. The results demonstrate that the activity of sodium channels contributes to effector roles of activated microglia.

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Section: Discussionmentioning

confidence: 99%

Sodium channel activity modulates multiple functions in microglia

Black

Liu

Waxman

2008

Glia

139

149

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“…"In vitro" studies have also demonstrated that human peripheral blood mononuclear cells (PBMC) isolated from healthy volunteers and exposed to CBZ showed no significant variation of natural killer (NK) cell activity (Margaretten et al, 1987).…”

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confidence: 99%

Immunologic Aspects of Carbamazepine Treatment in Epileptic Patients

et al. 1991

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Immune abnormalities have been found in epileptic patients receiving antiepileptic drugs (AEDs). Phenytoin (PHT) produces a decrease in serum IgA and IgM levels and a decrease in blastic transformation of circulating lymphocytes stimulated with phytohemoagglutinin (PHA). The effects of carbamazepine (CBZ) on the immune response are still conflicting. To elucidate the effects of CBZ on some immunologic parameters, serum concentrations of IgA, IgG, IgM, the phagocytosis and killing properties of polymorphonuclear leukocytes (PMNs), the cytotoxic activity of natural killer cells and the response of lymphocytes to mitogenic agents were studied. Forty healthy individuals and 39 epileptic patients treated with carbamazepine (CBZ) monotherapy (age range 18-40 years) entered the study. Student's t test was used to evaluate the data. CBZ had no effect on the serum immunoglobulin concentrations or on lymphocytic reactivity to phytohemoagglutinin (PHA) mitogen. CBZ produced a significant enhancement of phagocytosis and killing properties of PMNs and an increase in natural killer (NK) cell activity. Therefore, a negative effect of CBZ therapy on the immune system was not observed in this study.

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“…Although Margaretten et al (1987) found no significant effect on this parameter in vitro, it should be noted that the diluent used in this study for carbamazepine decreased natural killer cell activity compared with saline. Thus, carbamazepine seems to diverge markedly from phenytoin, which dose-dependently inhibited natural killer cell activity as well as antibody-dependent cell-mediated cytotoxicity in vivo and in vitro (Margaretten et al 1987;Thatcher et al 1982).…”

Section: 2 Carbamazepinementioning

confidence: 80%

Immunological Adverse Effects of Anticonvulsants

et al. 1993

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Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

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Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro*1

Cited by 33 publications

References 29 publications

Sodium channel activity modulates multiple functions in microglia

Sodium channel activity modulates multiple functions in microglia

Immunologic Aspects of Carbamazepine Treatment in Epileptic Patients

Immunological Adverse Effects of Anticonvulsants

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